This invention relates generally to portable devices and methods useful for optimizing the size distribution of a medical aerosol, and reducing the amount of variability arising from variations in ambient conditions. More specifically, this invention relates to battery powered, portable devices for controlling the temperature of air surrounding aerosol particles of drugs and delivering the drug to a specific area of the lung.
There are several known methods for the aerosolized delivery of drugs. In general, the methods include: (1) placing an aqueous formulation within a nebulizer device which by various mechanical means causes the drug formulation to be aerosolized in a continuous stream which is inhaled by the patient; (2) dry powder inhalers which create a fine powder of the drug and aerosolize the powder in a dust form which is inhaled; (3) metered dose inhalers which dissolve or disperse the drug in a low boiling point propellant; and (4) more current devices such as that disclosed within U.S. Pat. No. 5,660,166 issued Aug. 26, 1997 which force aqueous formulations through a nozzle to create an aerosol which is inhaled by the patient.
In accordance with each of the known methods for aerosolizing a drug it is important to produce an aerosol which has particles within a desired size range, e.g. 0.5 to 12.0 microns and more preferably 1.0 to 3.5 microns. In addition to producing small particles it is preferable to produce particles which are relatively consistent in size, i.e. produce an aerosol wherein a large percentage of the particles fall within the desired size range. In addition, it is desirable to produce an aerosol which has the property that the key measures of aerosol quality, such as particle size and dose emitted are not effected by ambient conditions such as temperature and or relative humidity. With any of the known methods for aerosol delivery of drugs there are difficulties with respect to making the particles sufficiently small. Along with these difficulties there are difficulties with respect to creating particles which are relatively consistent in size. These difficulties are particularly acute when attempting to provide for systemic delivery of an aerosolized drug. Efficient systemic delivery requires that the aerosol be delivered deeply into the lung so that the drug can efficiently reach the air/blood exchange membranes in the lung and migrate into the circulatory system.
Aerosol delivery to the lungs has been used for delivery of medication for local therapy (Graeser and Rowe, Journal of Allergy 6:415 1935). The large surface area, thin epithelial layer, and highly vascularized nature of the peripheral lung (Taylor, Adv. Drug Deliv. Rev. 5:37 1990) also make it an attractive site for non-invasive systemic delivery. Unlike other avenues of non-invasive delivery such as trans-dermal, nasal, or buccal, the lung is designed as a portal of entry to the systemic circulation. However, targeting the peripheral lung requires careful control of the aerosol particle size and velocity distributions, in order to by pass the exquisitely evolved particle filtering and clearing functions of the bronchial airways.
Many authors have reported results of experiments or mathematical models showing that micron sized particles are required for delivery to the lungs (c.f. Stahlhofen, Gebhart and Heyder, Am. Ind. Hyg. Assoc. J. 41:385 1980, or Ferron, Kreyling and Haider, J. Aerosol Sci. 19:611 1987). One example is the model of the Task Group on Lung Dynamics (Morrow et. al. Health Physics 12:173 1966). As FIG. 1 shows, under the assumptions of this model, particles of diameter less than xcx9c3.5 xcexcm are required to avoid the oropharynx and bronchial airways. FIG. 1 might suggest that the maximum efficiency of deposition of drugs delivered to the pulmonary region of the lung is limited to xcx9c60%. However, as can be seen in FIG. 2, efficiencies approaching 100% can be achieved by allowing the particles to settle gravitationally during a ten second breath hold (Byron, J. Pharm. Sci. 75:433 1986).
It has been demonstrated that ambient conditions can strongly effect the amount of aerosol particles less than 3.5 xcexcm emitted from aerosol generation device. One example is the work of Phipps and Gonda (Chest 97:1327-1332, 1990) showing that the amount of aerosol less than 3.5 xcexcm delivered by a aerosol drug delivery device changed from 33% to 73% when the relative humidity changed from 100% to 70%. Similar work with a dry powder (Hickey et al J. Pharm. Sci. 79, 1009-1011) demonstrated a change in the amount of aerosol less than 3.5 xcexcm from 9% to 42% when the ambient relative humidity changed from 97% to 20%. These data are tabulated in Table 1.
Many pharmaceutical compounds of a wide range of molecular weights are potential candidates for systemic delivery via the lung. Small molecules analgesics such as morphine or fentanyl could be delivered to pain patients, e.g. cancer or post-operative patients. Morphine has demonstrated bioavailability when delivered via the lung (S. J. Farr, J. A. Schuster, P. M. Lloyd, L. J. Lloyd, J. K. Okikawa, and R. M. Rubsamen. In R. N. Dalby, P. R Byron, and S. J. Farr (eds.), Respiratory Drug Delivery V, Interpharm Press, Inc., Buffalo Grove, 1996, 175-185).
Potent peptide hormones are available for a variety of therapeutic indications. Leuprolide, for example, is a GnRH super-agonist useful in the treatment of endometriosis and prostate cancer. Leuprolide also has potential applications in the field of breast cancer management and the treatment of precocious puberty. Calcitonin enhances metabolism and may be a useful therapeutic agent for the management of osteoporosis, a common complication of aging.
To treat conditions or diseases of the endocrine system, pharmaceutical formulations containing potent peptide hormones are typically administered by injection. Because the stomach presents a highly acidic environment, oral preparations of peptides are unstable and readily hydrolyzed in the gastric environment. Currently, there are no oral preparations of therapeutic peptide agents commercially available.
Both calcitonin and leuprolide can be administered nasally. (See Rizzato et al., Curr. Ther. Res. 45:761-766, 1989.) Both drugs achieve blood levels when introduced into the nose from an aerosol spray device. However, experiments by Adjei et al. have shown that the bioavailability of leuprolide when administered intranasally is relatively low. However, an increase in the bioavailability of leuprolide can be obtained by administering the drug into the lung. Intrapulmonary administration of leuprolide has been shown to be an effective means of non-invasive administration of this drug (Adjei and Garren, Pharmaceutical Research, Vol. 7, No. 6, 1990).
Intrapulmonary administration of drugs has the advantage of utilizing the large surface area available for drug absorption presented by lung tissue. This large surface area means that a relatively small amount of drug comes into contact with each square centimeter of lung parenchyma. This fact reduces the potential for tissue irritation by the drug and drug formulation. Local irritation has been seen with nasal delivery of insulin and has been a problem for commercialization of nasal preparations of that drug. It is a problem with peptide hormones that they are very potent with effects that are not immediately manifested. For example, therapy with leuprolide for prostate cancer does not typically produce any acute clinical effects. Similarly, prophylaxis against osteoporosis with calcitonin will not produce any acute symptoms discernible to the patient. Therefore, administration of each dose of these drugs must be reliable and reproducible.
A portable, self-contained device useful for controlling the temperature of the air surrounding an aerosolized drug formulation is provided. The temperature controlling device is comprised of a heating element (preferably in the form of a wire coil) which warms the air surrounding an aerosolized pharmaceutical formulation. The warming of the air results in evaporating liquid carrier from aerosol particles of a liquid formulation, thereby obtaining a smaller, more uniform particle size. Alternatively, or in addition, the warming of the air can prevent or impede the accumulation of water (which might condense from the air) on particles of a liquid formulation or especially a dry powder. Because warming of ambient air will always result in a reduced relative humidity, it is possible to ensure that only evaporation will occur, as differentiated from introducing aerosols into uncontrolled ambient air, where growth (i.e., condensation of water vapor on an aerosolized particle) or evaporation are generally possible. Thus the use of a temperature controller can reduce the dependence of particle size on ambient conditions. The results of such make it possible to more precisely target areas of the respiratory tract by adjusting particle size by warming the air.
To have practical utility any temperature controller to be used by patients administering inhaled drugs must be small, efficient, and highly portable. The invention preferably comprises a portable power source such as a battery (e.g. 10 AA or similarly sized batteries or less), a control circuit, a temperature sensing means, a relay, and a heating element. These components are preferably combined with an aerosol generating means which is most preferably the type which moves formulation through holes. The air surrounding the aerosol particles is preferably warmed to the extent that 50% or more of the carrier is evaporated away from the particles of an aqueous formulation. More preferably, the warming results in providing particles which are substantially dryxe2x80x94all free water being evaporated away. A very important aspect of the invention is in a temperature controller which achieves the desired effects while being powered only by a battery.
The heating element is preferably in the form of a wire coil of an alloy containing some or all of: nickel, chromium, copper, and iron and having a weight of about 5 grams (xc2x14 grams) and a gauge of about 26 (xc2x110 gauge). Alternatively, the heating element may be in the form of a stamped and/or folded metal sheet. Different types of heating elements could be used provided they meet certain criteria. It must be possible to heat the element with a portable battery source in a short period of time, e.g. one minute or less. The element is preferably capable of storing sufficient energy to warm the air (e.g. 0.5 to 4 liters or more of air) surrounding the aerosol particles sufficiently to evaporate all or most of the carrier, even at high ambient relative humidity. The element must also be capable of quickly releasing heat energy to the air, e.g. releasing 20 joules or more of energy in 10 seconds or less, preferably about 2.5 seconds or less. Stated functionally, the heating element must be able to absorb and then release heat energy in amount sufficient to control particle size for a useful aerosolized dose of formulation and that energy must be absorbed and released in a period of time which is sufficiently short to be practically used during aerosolized drug delivery.
Key to the functioning of the invention is the fact that the time for a heated object to cool off is significantly shorter in moving air than in still air. Thus it is possible to preheat the element over a period of time of 10-60 seconds and store the heat for a similar period of time, and then deliver the heat into moving air in a period of time of 1-10 seconds. The heating element must be able to deliver heat back to the air in a short period, e.g. a period which correspond to the length of a patient""s inhalation.
The invention increases the number and types of pharmaceutical formulations which can be administered efficiently and reproducibly by inhalation. More particularly, the invention makes it possible to inhale formulations which are intended for systemic delivery, including peptides such as insulin and analogs of insulin (e.g., insulin lispro). This is done by increasing the reproducibility of dosing by adjusting particle size to a consistent level in different surrounding humidities. Further, particular areas of the lung are targeted by (1) including aerosolized formulation in precisely determined volumes of air, (2) warming air surrounding the aerosolized formulation so as to evaporate carrier and reduce the particle size and/or to prevent water vapor in the air from condensing on particles, (3) excluding aerosolized formulation from other volumes of air delivered to the lung in order to correctly position an aerosol. Further, the heating means can be used with any type of means of generating an aerosol. More specifically, the heating means can be used with a nebulizer, a dry powder inhaler or metered dose inhaler. However, the major benefits of the invention are obtained when used with a device which creates aerosolized particles by moving liquid (aqueous or ethanolic) formulations through small holes to create particles (see U.S. Pat. No. 5,718,222 issued Feb. 17, 1998). All types of nebulizers benefit from the invention by reducing variable effects caused by the environment, e.g., changes in humidity.
The amount of energy added can be adjusted depending on factors such as the desired particle size, the amount of the carrier to be evaporated, the water vapor content (humidity) and temperature of the surrounding air, the composition of the carrier, and the region of the lung targeted.
To obtain reproducible, efficient systemic delivery it is desirable to get the aerosolized formulation deeply into the lung. This requires the delivery of the formulation in aerosol particles of diameter less than approximately 3.5 xcexcm. Direct generation of particles in this size range can be difficult, due to the large ratio of surface area to volume of these small particles. Energy may be added in an amount sufficient to evaporate all or substantially all the carrier from an aqueous aerosol and thereby provide particles of dry powdered drug or highly concentrated drug formulation to a patient which particles are (1) uniform in size regardless of the ambient humidity and temperature (2) preferably produced from a liquid formulation, and (3) smaller due to the evaporation of the carrier.
A primary object of the invention is to provide an air temperature controlling device comprised of a receptacle for holding a self-contained power source such as electric power cells forming a battery, a channel comprising an air flow path which includes an opening into which air can be inhaled and a second opening into which air is delivered and aerosol is generated, a heating element connected to the electrical contacts of the receptacle and positioned in a manner such that air flowing by the heating element flows through the channel, wherein the device is a hand-held, self-contained device having a total weight of one kilogram or less.
It is another object of the invention to provide such a device wherein the heating element is comprised of an alloy containing copper, chromium, iron and/or nickel which heating element is preferably in the form of a wire having a gauge in the range of about 16 to 36 weighing approximately 0.5 to 10 grams.
An important advantage of the invention is that the heating device can heat a sufficient amount of air so as to evaporate a sufficient amount of carrier on aerosolized particles to make the particles consistent in size and sufficiently small as to improve the repeatability and efficiency of drug delivery.
It is an object of this invention to provide a portable air temperature controlling device able to warm the air surrounding the particles of an aerosolized drug formulation.
It is a further object of the invention to provide a drug delivery device containing such a heating element which is heated by a portable, self-contained energy source.
It is a further object of the invention to provide methods of administering aerosolized drug formulations in which the air surrounding the aerosolized formulation is warmed using a portable air temperature controlling device.
An advantage of the present invention is that it can be used for ambulatory patients.
Another object of the invention is that it makes it possible to adjust particle size by adding energy to the air surrounding the particles in an amount sufficient to evaporate carrier and reduce total particle size.
Another object of the invention is that it reduces or eliminates the variability in particle size due to variations in ambient relative humidity and temperature by ensuring that the delivered particles are in the range of 1-3.5 xcexcm independent of ambient conditions. This object of the invention can apply equally well to aerosol generation devices that generate aerosols of liquid solutions of drug, liquid suspensions of drug, or dry powders of drug.
Another object is to provide a device for the delivery of aerosols which measures ambient humidity via a solid state hygrometer, and/or measures ambient temperature via a temperature sensor.
A feature of the invention is that drug can be dispersed or dissolved in a liquid carrier such as water and dispersed to a patient as dry or substantially dry particles.
These and other objects, advantages and features of the present invention will become apparent to those skilled in the art upon reading this disclosure in combination with drawings wherein like numerals refer to like components throughout.